Without being bound to theory, it is believed that norepinephrine transporter (NET), a 12 membrane spanning protein, located presynaptically on noradrenergic nerve terminals, plays a critical role in the regulation of the synaptic norepinephrine (“NE”) concentration via the reuptake of NE (R. D. Blakely et al., J. Exp. Biol, 196:263-281(1994); T. Pacholczyk et al., Nature, 350:350-354(1994); and S. G. Amara et al., Annu. Rev. Neurosci., 16:73-93(1993)). The NET is critical for the removal of NE from the extracellular space (J. Axelrod et al., Porg. Brain Res., 31:21-32(1969); H. Bonisch at al., Ann. Y. E Acad. Sci., 733: 193-202(1994)) and is a target for antidepressant drug actions (J. C. Nelso, Psychiatry, 46: 1301-1308(1999) and H. J. Moller, J. Clin. Psychiatry, 61 (SUPP.6):24-27(2000Ï).
Many antidepressant drugs act by binding serotonin transporters (“SERT”) and/or NET to increase serotonin and norepinephrine levels at neuronal synapses. While the role of SERTs in depression has long been explored, the NE system has also been proposed to be important in the treatment of depression. In the past, tricyclic antidepressant (“TCA”) compounds and monoamine oxidase inhibitors (“MAOI”) represented the major pharmacological treatments for this illness. Such drugs have the disadvantage of their low selectivity and interaction with several other types of receptors causing unwanted side effects (A J. Frazer, J. Clin. Psychiatry, 58(SUEPJL}:9-25(1997)).
In an attempt to provide improved medications, selective serotonin reuptake inhibitors (“SSR1”) such as fluoxetine, nisoxetine, reboxetine, and their analogues (shown below) have been developed to treat depression.

Some of these compounds are quite effective in certain patient populations. However, their use is often limited by side effects, particularly those thought to be mediated by their anticholinergic properties (R. Valentino et al., Ann. N. Y. Acad. Sci., 697: 171-187(1993); R. Mongeau et al., Brain Res. Rev., 23: 145-195(1997)). No simple increase or decrease in neuronal activity is likely to be the primary cause of depression. It may be that a complex dysregulation of the Locus Coeruleus-Norepinephrine system may play an important role in depression (K. J. Ressler et al., Biol. Psychiatry, 46: 1219-1233(1999)). Different studies had significant differences in NE metabolites and changes in receptor populations (D. Charney, J. Clin. Psychiatry, 59: 1 1-14(1998); B. Leonard, J. Psychopharmacol., 11:s39-s47(1997); A. Schatzberg et al., “Psychopharmacology: The Fourth Generation of Progress”, pp. 911-920(1995)).
In addition to depression, the role of NET has also recently been implicated in thermoregulatory dysfunctions such as vasomotor symptoms, e.g., hot flashes experienced by naturally, chemically or surgically induced menopausal women. Although the physiology of hot flashes is still poorly understood today, studies have revealed an association of increased levels of norepinephrine in the preoptic hypothalamus in the brain to hot flashes. There is also supportive evidence for the role of norepinephrine (NE) and serotonin (5-HT) in thermoregulation. Compounds that modulate norepinephrine levels are therefore useful for the treatment of vasomotor symptoms.
The availability of new imaging tools such as selective positron emission tomography (“PET”) and/or single photon emission computed tomography (“SPECT”) radioligands for mapping specific transporter systems have significantly advanced the understanding of the field of depression and will be similarly useful in the understanding of other NET/SERT mediated disorders such as dysphoria, anxiety, sleep disorders, gastric motility disorders, sexual dysfunction, brain trauma, memory loss, appetite disorders, bulimia, obesity, substance abuse, alcoholism, tobacco addiction, obsessive-compulsive disease, panic disorder, premenstrual syndrome, migraine, bipolar disorders, neuropathic pain (e.g., chronic pain, e.g., fibromyalgia), attention deficit hyperactive disorder (ADHD), Alzheimer's Disease, and vasomotor symptoms, e.g., hot flashes, especially anxiety and depression. PET and SPECT make possible the direct study and quantification of neurotransmitter systems in the human brain and better understand psychiatric diseases. These target-specific radiotracers facilitate the development of therapeutic agents for depressive illness, optimize the therapeutic dosage, and monitor the efficacy of treatment. Despite recognition of the high importance of the NET as a site of action of many old (e.g. desipramine) and new (e.g. reboxetine) antidepressant drugs in the brain, and even though the NET has long been recognized in relation to the pathophysiology and treatment of ADHD, substance abuse, and depression, there have been relatively few attempts to develop radiotracers for imaging NET in vivo in the central nervous system (“CNS”), either by PET or SPECT (Wilson et al., Nuclear Medicine and Biology, 30:85-92(2003)).
Hake et al., Nucl. Med. Biol., 16:771-574(1989) reported the synthesis of [11C]nisoxetine as a PET ligand which demonstrated only modest specific binding in mice. Kung et al., Eur. J. Nucl. Med. Molecular Imaging, 26:844-853(1999) synthesized an iodinated derivative of tomoxetine that showed a low degree of saturable binding in vivo in rat brain, and very high lung uptake. Chumpradit et al., J. Med. Chem., 35:4492-4497(1992) and Koch et al., Neuropeychopharmacology, 27:949-959(2002) demonstrated in vitro that (R)-derivatives of fluoxetine had higher affinity to NE uptake sites than corresponding (S)-derivatives. Stolin et al., Chirality, 7:285-289(1995) showed that the (S, S) enantiomer of reboxetine is more potent than its (R,R) enantiomer (IC50 3.6 nM and 85 nM respectively) in inhibiting the NE uptake in rat hypothalamic synaptosomes. Ding et al., Synapse, 50:345-352(2003) reported an evaluation of the individual enantiomers of reboxetine methyl analog [11C]MRB as radioligands for PET imaging studies of NET systems in baboons, both in brain and in peripheral organs. However, the results were not optimal due to high non-specific biding in vivo. The MRB tracer also displayed unexpected high uptake in striatum, a region that contains low levels of NET, and some binding to sites other than NET is suspected. Van Dort et al., Nuclear Medicine and Biology, 24:707-711(1997) has reported the radiosysnthesis of [11C]desipramine but no in vivo data have been published yet.
There remains a need for a NET/SERT ligand with moderate lipophilicity and high binding affinity. Although the affinity of nisoxetine for NET is high, its lipophilicity is also undesirably high at log P>3.5.